Biology subjects

Bang-Andersen, B.

Publications and source records attributed to Bang-Andersen, B..

3 recordsLinked to original sources

bioRxiv2026

5-MOP: a novel and selective colony stimulating factor-1 receptor (CSF1R) radiotracer

Colony stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor that is expressed exclusively in microglia within the CNS. Its endogenous ligands, colony stimulating factor-1 (CSF1) and interleukin-34 (IL-34), are released from neurons, positioning CSF1R as a key mediator receptor of neuron-glia communication. CSF1R is considered not only a potential drug target, but also a biomarker of neuroinflammation. From that perspective, selective radioligands for neuroimaging are of great interest for imaging neuroinflammation and determining drug occupancy. In this study, we have validated the binding characteristics of a CSF1R inhibitor, 4-((5-MethOxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine (5-MOP) as a novel CSF1R radioligand, by performing in vitro saturation binding experiments in human and murine tissues. 5-MOP was found to be selective for CSF1R among a broad range of kinases. Autoradiography revealed that [3H]5-MOP binds with high affinity (KD = 9.8 nM) to a single saturable binding site in human meningioma tissues, and this binding was displaced with known CSF1R inhibitors, including CPPC, sCSF1inh and GW-2580. In contrast, CPPC, which has been extensively used as a CSF1R radioligand showed substantial cross-reactivity to other brain kinases, including Trk A/B/C, and [3H]CPPC could only be displaced with CPPC itself, not by other ligands, including 5-MOP. These results identify [3H]5-MOP as the most selective radioligand currently available, enabling accurate detection of drug occupancy and activated microglia. Significance of the studyThis study identifies and validates a novel selective radioligand that binds CSF1R with high selectivity and low nanomolar affinity. Because CSF1R is selectively expressed in activated microglia, this radioligand could be useful for detecting neuroinflammatory activity.

neuroscience↗

bioRxiv2025

T-401 binding to monoacylglycerol lipase (MAGL) in the brains of patients and mice with temporal lobe epilepsy

Monoacylglycerol lipase (MAGL) inhibitors are considered as drug candidates for epilepsy. In order to determine the level of MAGL and evaluate changes in the epileptic brain, we have validated and used autoradiography and the MAGL radiotracer [3H]T-401 on resected temporal neocortex specimens obtained from patients with temporal lobe epilepsy and in brains from mice with chronic reoccurring seizures. Saturation experiments revealed a KD around 4 nM for the human temporal cortex and 7 nM for the mouse brain. In the human brain, binding of [3H]T-401 was detected mostly in the grey matter, and in the subcortical white matter in lower amounts. The levels were strongly correlated in the two cortical compartments. The level of [3H]T-401 binding in the human temporal cortex varied about a 4-fold among the patients, but was not correlated to either epilepsy duration or the age of the patients. In the epileptic mouse brain, a significant reduction was observed bilaterally in the hippocampus, as well as in other cortical regions, including the temporal cortex. Interestingly, a highly significant negative correlation was seen between MAGL and binding to the translocator protein 18 kDa (TSPO) expressed in glia. These data support the presence of MAGL in neuronal and non-neuronal cells, and indicate that MAGL levels in the brains of either patients with epilepsy or mice after intra-hippocampal kainite injection are reduced not only in the epileptic zone in the hippocampus, but more widespread in the brain.

neuroscience↗

bioRxiv2024

Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3 receptors

Vortioxetine (VTX) is a recent antidepressant that targets a variety of serotonin receptors. We investigate the drugs molecular mechanism of operation at serotonin 5-HT3 receptors (5-HT3R), which features two mysterious properties: VTX acts differently on rodent and human 5-HT3R; VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist bound-like state of the human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.

biochemistry↗